The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study

Collins U. Ibeji, Monsurat M. Lawal, Gideon F. Tolufashe, Thavendran Govender, Tricia Naicker, Glenn E.M. Maguire, Gyanu Lamichhane, Hendrik G. Kruger, Bahareh Honarparvar

Research output: Contribution to journalArticle

Abstract

β-lactam antibiotics, which are used to treat infectious diseases, are currently the most widely used class of antibiotics. This study focused on the chemical reactivity of five- and six-membered ring systems attached to the β-lactam ring. The ring strain energy (RSE), force constant (FC) of amide (C−N), acylation transition states and second-order perturbation stabilization energies of 13 basic structural units of β-lactam derivatives were computed using the M06-2X and G3/B3LYP multistep method. In the ring strain calculations, an isodesmic reaction scheme was used to obtain the total energies. RSE is relatively greater in the five-(1a–2c) compared to the six-membered ring systems except for 4b, which gives a RSE that is comparable to five-membered ring lactams. These variations were also observed in the calculated inter-atomic amide bond distances (C−N), which is why the six-membered ring lactams C−N bond are more rigid than those with five-membered ring lactams. The calculated ΔG # values from the acylation reaction of the lactams (involving the S−H group of the cysteine active residue from L,D transpeptidase 2) revealed a faster rate of C−N cleavage in the five-membered ring lactams especially in the 1–2 derivatives (17.58 kcal mol −1 ). This observation is also reflected in the calculated amide bond force constant (1.26 mDyn/A) indicating a weaker bond strength, suggesting that electronic factors (electron delocalization) play more of a role on reactivity of the β-lactam ring, than ring strain.

Original languageEnglish (US)
JournalChemPhysChem
DOIs
StatePublished - Jan 1 2019

Keywords

  • activation energy.
  • force constant (FC)
  • ring strain energy (RSE)
  • transition state (TS)
  • β-lactam antibiotics

ASJC Scopus subject areas

  • Atomic and Molecular Physics, and Optics
  • Physical and Theoretical Chemistry

Fingerprint Dive into the research topics of 'The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study'. Together they form a unique fingerprint.

  • Cite this

    Ibeji, C. U., Lawal, M. M., Tolufashe, G. F., Govender, T., Naicker, T., Maguire, G. E. M., Lamichhane, G., Kruger, H. G., & Honarparvar, B. (2019). The Driving Force for the Acylation of β-Lactam Antibiotics by L,D-Transpeptidase 2: Quantum Mechanics/Molecular Mechanics (QM/MM) Study. ChemPhysChem. https://doi.org/10.1002/cphc.201900173